There is growing evidence that the lateral olivocochlear (LOC) pathway modulates auditory nerve (AN) activity. We contributed to this body of work by selectively lesioning LOC innervation at its origin (Le Prell et al. 2003), or its termination (Le Prell et al. 2004). Our studies, as well as earlier investigations in which both LOC and medial olivocochlear (MOC) pathways were disrupted (Liberman 1990; Walsh et al. 1998; Zheng et al. 1999), suggest the net effect of LOC innervation is enhancement of spontaneous and sound-driven auditory nerve fiber (ANF) activity. Depression of AN activity after LOC disruption has been attributed to loss of one or more excitatory transmitters. Recently, Maison et al. (2003) presented evidence that calcitonin-gene-related peptide (CGRP) could modulate the excitatory LOC effects observed in the above investigations. The finding that alphaCGRP-null mice have depressed amplitude of the sound-evoked auditory brainstem response (ABR, see Maison et al. 2003) may reflect direct enhancement of driven AN activity by CGRP. However, changes in driven activity might also be a consequence of changes in spontaneous activity. In the amphibian lateral line, CGRP increases spontaneous activity (Adams et al. 1987; Sewell & Starr 1991; Bailey & Sewell 2000a; 2000b). If CGRP similarly enhances spontaneous activity of ANFs, one might predict enhanced sound-driven ANF activity as ANFs with higher spontaneous rates of firing have lower thresholds and higher driven firing rates. To distinguish among competing hypotheses, and determine the extent to which CGRP effects are similar in the amphibian and mammalian systems, it is essential that we identify the effects of CGRP agonists and antagonists on spontaneous and driven activity in the mammalian cochlea. This investigation specifically addresses several important issues using single unit and whole nerve potentials. First, it directly addresses the prediction that activation (or blockade) of CGRP receptors modulates spontaneous and sound-evoked ANF activity (Specific Aim 1). Second, these experiments will identify functional changes in temporal resolution and changes in response to signals in noise, providing important new data on the role of CGRP in LOC function. Additional experiments (Specific Aim 2) will identify the extent to which changes induced by CGRP manipulation mimic the effects of disrupting all (or most) of the LOC system using MPTP (a dopaminergic neurotoxin that we have used previously to disrupt LOC innervation, see Le Prell et al. 2004).